DESCRIPTION Tropism of HIV for macrophages contributes to primary HIV pneumonia whereas replication in lymphocytes leads to immunosuppression and secondary opportunistic infections. The two main forms of primary HIV-induced pneumonia are lymphocytic interstitial pneumonia (LIP) and diffuse infiltrative lymphocytosis syndrome (DILS), and individuals with these conditions survive longer and have fewer opportunistic infections than those who do not. Like HIV, SIV replicates in both CD4+ lymphocytes and monocytes/macrophages, but is mainly detected in cells of macrophage lineage in the lung. Specific strains of SIV cause lesions in the lungs of juvenile macaques that resemble HIV lymphoid interstitial pneumonia, and macaques with these lesions also survive longer. This application proposes a multidisciplinary approach to identify viral and host factors that contribute to pulmonary disease. The hypothesis to be tested in these studies is that while many viral strains enter the lung in infected blood, only certain macrophage-tropic strains establish themselves in pulmonary tissue, possibly related to expression of specific viral co-receptors in the lung. It also hypothesized that the lymphocytic pneumonia is indicative of effective immunologic restraint of macrophage-tropic viral burden and thus improved prognosis. For these studies, macaques will be inoculated with SIV and euthanized during the initial stage of viral replication (3 weeks p.i.), during the stage of clinical quiescence (3 months p.i.), and during terminal clinical diseases. 1) Pulmonary and systemic immune responses, pulmonary lesions, and viral load will be measured in these macaques to determine at what stage of infection lymphocytic interstitial pneumonia appears, whether lymphocytic interstitial pneumonia is indicative of effective pulmonary antiviral immune responses, and whether the effectiveness of pulmonary immune responses predicts outcome of infection. 2) The levels of expression of pro-inflammatory molecules (cell adhesion molecules, chemokine receptors, chemokines, and cytokines) in lung tissue and bronchoalveolar cells will be measured throughout SIV infection and correlated with pulmonary and peripheral viral load with host immune responses. 3) The viral strains and genotypes that replicate productively in lungs of animals infected with SIV will be identified to determine if specific virus strains are associated with the development of LIP. Replication of viruses isolated from the lung of infected macaques in primary cultures of peripheral blood-derived macrophages and alveolar macrophages will be measured. Virus isolates from lung will be characterized for co-receptor usage (chemokine receptors) to determine if differences exist between macrophage-tropic viruses isolated from the peripheral blood and the lung. 4) The cytokines, chemokines, and chemokine receptors that are expressed in alveolar macrophages and peripheral blood-derived macrophages infected with different strains of virus will be identified.